Non-epithelial ovarian cancer Rachel W. Miller Assistant Professor Gynecologic Oncology University of Kentucky Markey Cancer Center

Types of Ovarian Cancer Epithelial Ovarian Cancer (90%) Serous/Papillary serous (80%) Mucinous (10%) Endometrioid (10%) Clear Cell Brenner Tumors *Borderline Tumors* Germ Cell Tumors Dysgerminoma Yolk Sac Tumors/Endodermal sinus tumor Embryonal Carcinoma Choriocarcinoma Teratomas Sex-cord Stromal Tumors Granulosa Cell Tumors Fibrosarcoma Sertoli-Leydig Tumors

Germ Cell Tumors 20% of all ovarian tumors 2-3% of ovarian malignancies Presentation at young age (early 20’s) Tumor markers hCG αFP LDH

Evolution of Germ Cell Tumors Dysgerminoma Embryonal Carcinoma Polyembryoma Teratoma Endodermal sinus tumor Choriocarcinoma Germ cell Morula Blastula Embryo Yolk sac

Ovarian Germ Cell Tumors

Germ Cell Tumors Dysgerminoma Endodermal sinus tumor Teratoma Immature Mature Struma ovarii Carcinoid Choriocarcinoma Embryonal carcinoma Polyembryoma Mixed GCT Combo GCT/Stromal Gonadoblastoma Other Carcinoid develops in mature teratomas, usually in older women. Can have malignant potential, but generally have an indolent course and rarely metastasize.

Dysgerminoma Lance Armstrong Incidence 10-15% bilaterality 1-2% of ovarian tumors 3-5% of ovarian malignancies 40% of all GCT Peak incidence age 19 67% stage IA 10-15% bilaterality 20% in “normal appearing” opposite ovary

Dysgerminoma Large, white to grey, fleshy, lobulated masses.

Dysgerminoma No or very little areas of hemorrhage or necrosis – if these are present, think about a mixed germ cell tumor.

Dysgerminoma Presentation Tumor markers Survival Solid, lobulated, and can be large 15% associated with mature cystic teratoma Associated with gonadal dysgenesis and gonadoblastoma High growth fraction, lymphatic spread Tumor markers LDH, placental alkaline phosphatase Survival Overall =86% Stage I =90%

Dysgerminoma Fertility-sparing surgery Radiosensitive Chemotherapy 85% of patients are younger than 35 yo Consider uterine preservation (IVF) Radiosensitive Chemotherapy Combination, dose-intense regimen

Dysgerminoma Large, round, ovoid or polygonal cells Nest and cords of primitive appearing germ cells Lymphatic space invasion is common

Dysgerminoma Incidence Survival Stage IA 70% 92% 10-year Stage IB 10% >90% 5-year Stage II, III 15% Stage IV 5% 80%

Endodermal Sinus Tumor Presentation 20% of all GCT Median age 19 yo Abdominal pain, large mass 10-30 cm common Very rapid growth, intra-abdominal and hematological spread Tumor marker: AFP, α1 antitrypsin Synonyms Yolk sac tumor Survival Overall survival =70% Stage I =90%

Endodermal Sinus Tumor Solid tumor with hemorrhage and gelatinous necrosis on cut surface Microscopy Hyaline globules Reticular Pattern Schiller-Duval bodies Single blood vessel surrounded by neoplastic cells

Endodermal Sinus Tumor Hyaline globules → α1 anti-trypsin

Endodermal Sinus Tumor Schiller-Duval bodies

Teratomas Immature Mature Specialized Struma ovarii Carcinoid

Immature Teratoma Presentation 20% of all GCT 75% in first 2 decades of life 12-15% bilateral 60-70% are Stage I Rarely produce tumor markers: αFP and CA-125 Grade is determined by % immature neural tissue Stage IA grade 1 → no adjuvant therapy Survival Overall =63% Stage I =75%

Immature Teratoma Solid with cystic areas. Cut surface is soft fleshy or encephaloid.

Immature Teratoma Primitive neural elements

Immature Teratoma Grade Scully Norris 1 2 3 Well differentiated Well differentiated All mature; rare mitoses 1 Well differentiated; rare embryonal tissue Some immature and neuroepithelium 2 Moderate embryonal; atypia and mitoses Immature neuroepithelium ≤ 3 lpf 3 Large embryonal; atypia and mitoses Immature neuroepithelium in ≥ 4 lpf

Significance of Grading Grade Number Tumor Deaths 1 22 4 (18%) 2 24 9 (37%) 3 10 7 (70%)

Mature Teratoma 5-25% of all ovarian tumors 10-20% bilateral Most common ovarian tumor of young women Sonography Complex, cystic and solid Fat/fluid or hair/fluid level, calcifications High MI score 1-2% with malignant degeneration Rokitansky’s protuberance Squamous cell cancers possible

Mature Teratoma

Mature Teratoma Sebaceous glands

Mature Teratoma Intestinal gland formation

Specialized Teratomas Struma ovarii 2-3% of all teratomas 25-35% have symptoms of hyperthyroidism Usually benign, but may undergo malignant transformation Carcinoid tumors Associated with GI or respiratory epithelium Primary ovarian tumors are rare (N=50) Often older postmenopausal women 1/3 have carcinoid syndrome from serotonin Symptoms resolve with excision 5-hydroxyindoleacetic acid in urine

Struma Ovarii Follicles contain vividly eosinophilic, acellular colloid Variation in follicular size is typical Can have rich vascularity

Ovarian Carcinoid Insular pattern Round uniform cells Fibroconnective tissue background 80% with neurosecretory granules

Choriocarcinoma Presentation Tumor marker Uncommon, aggressive tumor Often part of mixed GCT Consider met from gestational chorioCA Mean age 20 yo, children common Half of premenarchal → precocious puberty Tumor marker hCG

Choriocarcinoma Cytotrophoblast Syncitiotrophoblast Hemorrhage Smaller cells Smaller nuclei Syncitiotrophoblast Larger cells Eosinophilic cytoplasm Bizarre nuclei Hemorrhage Syncitiotrophoblast

Embryonal Carcinoma Presentation Tumor markers: hCG, αFP Survival Mean age < 30 yo Only 4% of GCT and often part of mixed tumor 60% Stage IA Poorly differentiated germ cell tumor Aggressive, intra-abdominal spread and mets common Tumor markers: hCG, αFP Survival Overall =40% Stage I =75%

Embryonal Carcinoma Large, primitive cells Papillary or gland-like formation, occasional Sheets and ribbons

Polyembryona Best classified as a mixed tumor Never found in pure form Fewer than 50 cases All under age 40 Resembles embryonal carcinoma Embryo days 13-15 Treated like other mixed GCT Tumor markers: hCG, αFP

Mixed GCT Embryonal and Choriocarcinoma

Gonadoblastoma Combined Germ Cell / Sex Cord Stromal Tumor Presentation Age 1-38 Small tumors Phenotypic ♀ with virilization 90% have Y chromosome 22% from streak gonads Bilaterality 30-50% Check chromosomes for dysgenic gonads BSO if Y present If testicular feminization syndrome, await puberty before BSO

Gonadoblastoma Large germ cells, clear cytoplasm Nests of primordial germ cells surrounded by specialized stromal cells Associated sex cord stromal cells Gonadoblastoma Dysgerminoma

Tumor Markers Germ Cell Tumors Histology AFP hCG LDH PLAP CA-125 Dysgerminoma - + Endodermal sinus tumor Immature teratoma Embryonal CA ChorioCA

Germ Cell Tumors Treatment Surgery Importance of staging in early disease Fertility-sparing surgery often required Can preserve uterus for future IVF, even if BSO Debulking improves outcome

Chemotherapy Germ Cell Tumors BEP Bleomycin 20 U/m2 weekly x 9 Etoposide 100 mg/m2 days 1-5 q 3 weeks x 3 Cisplatin 20 mg/m2 days 1-5 q 3 weeks x 3 VAC Vincristine 105 mg/m2 weekly x 12 Act D 0.5 mg days 1-5 q 4 weeks Cytoxan 5-7 mg/kg days 1-5 q 4 weeks VBP Vinblastine 12 mg/m2 q 3 weeks x 4 Bleomycin 20 U/m2 weeks x 7, 8 on week 10

Sex-cord Stromal Tumors Fibroma Granulosa cell tumors Inhibin, CA-125 Sertoli-Leydig tumors CA-125, αFP, sTest Steroid cell tumors sTest (50-75% virilized) Gynandroblastoma ♀ and ♂ components

Fibroma

Granulosa Cell Tumor Presentation Estrogen excess and the endometrium Adult (95%) and juvenile types Solid and/or cystic- variable Estrogen, occasional androgen 80% palpable on examination Hemoperitoneum in 15% 80-90% Stage I Low grade, late relapse Estrogen excess and the endometrium 25% proliferative 55% hyperplastic 13% adenocarcinoma

Granulosa Cell Tumor Treatment Juvenile High cure rate Adult Resection Chemotherapy BEP Carboplatin and Taxol GnRH analogs

Granulosa Cell Tumor

Granulosa Cell Tumor

Granulosa Cell Tumor

Granulosa Cell Tumor Call-Exner bodies

Sertoli-Leydig Tumors Benign Sertoli cell tumors→ no hormones Leydig tumors→ testosterone Potentially Malignant Sertoli-Leydig tumors Arrhenoblastoma, androblastoma Grade 3 44% five-year survival Grade % Cancer 1 2 10 3 60

Sertoli-Leydig Tumor Well-differentiated tubules

Germ Cell and Stromal Tumors of the Ovary Treatment Summary Germ Cell and Stromal Tumors of the Ovary

Endodermal sinus tumor Embryonal carcinoma Malignant teratoma Dysgerminoma USO staging if possible BEP x 3 cycles if stage II-IV Endodermal sinus tumor Debulk but preserve fertility BEP x 3-4 cycles Embryonal carcinoma As above Malignant teratoma BEP or VAC x 3-4 cycles Granulosa cell tumor USO if young o/w TAH/BSO GnRH agonists for advanced ds. Sertoli-leydig cell

Summary Common in young women Tumor markers Treatment Fertility-sparing surgery Chemosensitive→ BEP for 3-6 cycles Radiosensitive No adjuvant chemo for: Stage I pure dysgerminoma Stage IA grade 1 immature teratoma